Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma.

Cowburn, Andrew S.; Sładek, Krzysztof; Soja, Jerzy; Adamek, Lukasz; Nizankowska, E; Szczeklik, A; Bk, Lam; Penrose, John F.; Austen, Frank K.; Holgate, Stephen T.; Sampson, Anthony P.

doi:10.1172/jci620

Cited by 525 publications

(468 citation statements)

References 69 publications

(93 reference statements)

Supporting

Mentioning

422

Contrasting

Unclassified

Order By: Relevance

“…In humans, it has been suggested that increased production of cysteinyl-LT correlates with susceptibility to aspirin-intolerant asthma (37,38). Recent studies have shown that variations in the synthesis of cysteinyl-LT result from a polymorphism in the LTC 4 synthase gene promoter, which causes constitutive overexpression of this enzyme in aspirin-sensitive patients (37)(38)(39)(40). Differing expression levels of LTC 4 synthase may account for variability observed in the response to LT inhibitors used in the treatment of asthma (37).…”

Section: Discussionmentioning

confidence: 99%

Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Goulet

Byrum

Key

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

Leukotrienes (LT) are potent lipid mediators synthesized by the 5-lipoxygenase pathway of arachidonic acid (AA) metabolism. LT have been implicated in a broad spectrum of inflammatory processes. To investigate the influence of genetic factors on the contribution of LT to acute inflammation, we generated congenic 5-lipoxygenase-deficient 129, C57BL/6 (B6), and DBA/1Lac (DBA) mouse lines. Topical application of AA evoked a vigorous inflammatory response in 129 and DBA mice, whereas only a modest response was seen in B6 animals. The response to AA in 129 and DBA strains is LT dependent. In contrast, LT make little contribution to this response in B6 mice. AA-induced inflammation in B6 mice is prostanoid dependent, since this response was substantially reduced by treating B6 mice with a cyclooxygenase inhibitor. These data suggest that prostanoids are essential for AA-induced cutaneous inflammation in B6 mice, whereas LT are the major mediators of this response in 129 and DBA strains. In contrast, the response to AA in the peritoneal cavity is robust in the 129 and B6 strains, but was significantly blunted in DBA mice, showing that strain differences in the response to AA are tissue specific. Variations in these and other experimental models of inflammation appear to correlate directly with the ability of a particular mouse strain and a specific tissue to respond to LT, specifically LTC4. Taken together, these findings indicate that the relative contribution of prostanoids and LT to inflammatory responses is variable not only between strains but also between different tissues within these inbred mouse lines.

show abstract

Section: Discussionmentioning

confidence: 99%

Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Goulet

Byrum

Key

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Ptges −/− mice develop marked eosinophildominated bronchovascular cellular infiltrates (>75% of BAL fluid cells) with lesser numbers of neutrophils (28,35). AERD is also associated with marked eosinophilia of the respiratory mucosa (44), often without evidence of sensitization to allergens. Because there is no method to elicit eosinophilic inflammation in mice independently of allergen, we elicited eosinophilic pulmonary inflammation in WT and ptges −/− mice with Df and challenged with Lys-ASA to determine whether impaired inducible PGE 2 generation permitted AERD-like physiology.…”

Section: Deletion Of Hematopoietic Ep 2 Receptors Partially Reproducementioning

confidence: 99%

“…The comparatively modest effect of anti-IL-5 may reflect incomplete depletion of eosinophils from the airway (as described in humans with asthma) (57). Alternatively, eosinophils may contribute to baseline cysLT generation (44), whereas other cells provide cysLTs during the reaction.…”

Section: Deletion Of Hematopoietic Ep 2 Receptors Partially Reproducementioning

confidence: 99%

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Liu

Laidlaw

Katz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

108

105

View full text Add to dashboard Cite

Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, tissue eosinophilia, overproduction of cysteinyl leukotrienes (cysLTs), and respiratory reactions to nonselective cyclooxygenase (COX) inhibitors. Ex vivo studies suggest that functional abnormalities of the COX-2/microsomal prostaglandin (PG)E 2 synthase-1 system may underlie AERD. We demonstrate that microsomal PGE 2 synthase-1 null mice develop a remarkably AERD-like phenotype in a model of eosinophilic pulmonary inflammation. Lysine aspirin (Lys-ASA)-challenged PGE 2 synthase-1 null mice exhibit sustained increases in airway resistance, along with lung mast cell (MC) activation and cysLT overproduction. A stable PGE 2 analog and a selective E prostanoid (EP) 2 receptor agonist blocked the responses to Lys-ASA by ∼90%; EP 3 and EP 4 agonists were also active. The increases in airway resistance and MC products were blocked by antagonists of the type 1 cysLT receptor or 5-lipoxygenase, implying that bronchoconstriction and MC activation were both cysLT dependent. Lys-ASA-induced cysLT generation and MC activation depended on platelet-adherent granulocytes and T-prostanoid (TP) receptors. Thus, lesions that impair the inducible generation of PGE 2 remove control of platelet/granulocyte interactions and TP-receptor-dependent cysLT production, permitting MC activation in response to COX-1 inhibition. The findings suggest applications of antiplatelet drugs or TP receptor antagonists for the treatment of AERD.A spirin-exacerbated respiratory disease (AERD) affects 5-10% of all adults with asthma (1-3), ∼30% with severe asthma (4), and ∼40% with refractory chronic hyperplastic sinusitis (5). It involves severe eosinophilic respiratory tract inflammation and is defined by bronchoconstriction following the ingestion of nonselective COX inhibitors (6). Cysteinyl leukotrienes (cysLTs) (LTC 4 , LTD 4 , and LTE 4 ) drive these reactions, as well as some of the chronic features of AERD (7,8). CysLTs derive from arachidonic acid metabolized by 5-lipoxygenase (5-LO) to LTA 4 , conjugated to reduced glutathione by leukotriene C 4 synthase (LTC 4 S) to LTC 4 in mast cells (MCs), eosinophils, basophils, macrophages, and granulocyte-platelet complexes (9). After export, LTC 4 is converted sequentially to LTD 4 and LTE 4 . CysLTs induce bronchoconstriction (10, 11), tissue eosinophilia (12), and remodeling (13) through G-protein-coupled receptors (GPCRs) expressed by structural and hematopoietic cells (14-16). Individuals with AERD display higher urinary levels of LTE 4 than do aspirin-tolerant asthmatic (ATA) control subjects (17). Reactions to aspirin or other nonselective COX inhibitors are accompanied by marked further increases in urinary levels of LTE 4 and can be blocked by pretreatment with the 5-LO inhibitor zileuton or with antagonists of the type 1 receptor for cysLTs (CysLT 1 R) (18,19). The dependency on COX products to maintain homeostasis over 5-LO activity is a unique feature of AERD. Remarkably, subjects with AERD can tolerate selective ant...

show abstract

“…However, we found no significant associations between the phenotype of AIA and these two polymorphisms or their haplotypes in this study, and no significant differences were noted with other clinical parameters. It has been reported that LTC4S was expressed five times more strongly in bronchial biopsies from AIA patients compared to ATA and normal controls (Cowburn et al 1998). Sanak et al (1997Sanak et al ( , 2000 showed that AIA was associated with the genetic polymorphism of LTC4S -444A>C, which has an additional responsive element to histone H4 transcription factor-2, and increases the transcription rate of the gene in vitro and in vivo in a Polish population.…”

Section: Discussionmentioning

confidence: 98%

Lack of an Association between a Newly Identified Promoter Polymorphism (-1702G > A) of the Leukotriene C4 Synthase Gene and Aspirin-Intolerant Asthma in a Korean Population

Choi

Kim

Bae

et al. 2006

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

Aspirin-intolerant asthma (AIA) is a distinct clinical syndrome that refers to the development of bronchoconstriction in asthmatic individuals following the ingestion of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). It is widely recognized that increased cysteinyl leukotriene (cysLT) biosynthesis is associated with the development and progression of AIA. Leukotriene C4 synthase (LTC4S) is the terminal enzyme in cysLT production and is a strong candidate gene in the pathogenesis of aspirin-intolerant asthma (AIA). In this paper, we report a new single nucleotide polymorphism (SNP) of the LTC4S promoter, -1702G>A, in AIA patients and evaluate its genetic role in the association with the LTC4S -444 A>C polymorphism. We enrolled 110 AIA patients, 125 aspirin-tolerant asthma (ATA) patients, and 125 normal controls. SNP genotyping of the LTC4S-1702G>A and -444A>C polymorphisms was performed using SNP-IT ™ assays. Haplotype analyses were performed using Haploview version 2.05, which is based on an estimation-maximization (EM) algorithm. There were no significant differences in the allele or genotype frequencies of the LTC4S -1702G>A and -444A>C polymorphisms among the three groups ( p > 0.05), with no significant differences in the observed haplotype frequencies ( p > 0.05). Moreover, no significant associations were found between the genotype of each SNP in AIA patients with the clinical characteristics, including a forced expiratory volume in one second (FEV 1 ) %, a provocation concentration of methacholine to induce more than 20% decrease of FEV 1 (PC 20 ) to methacholine, and serum total IgE levels ( p > 0.05). These results indicate that there is no association between these two promoter polymorphisms of LTC4S and the phenotype of AIA in a Korean population.aspirin-intolerant asthma; genetic polymorphism; leukotriene C4 synthase

show abstract

Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma.

Cited by 525 publications

References 69 publications

Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Lack of an Association between a Newly Identified Promoter Polymorphism (-1702G > A) of the Leukotriene C4 Synthase Gene and Aspirin-Intolerant Asthma in a Korean Population

Contact Info

Product

Resources

About

Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma.

Cited by 525 publications

References 69 publications

Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Genetic Factors Determine the Contribution of Leukotrienes to Acute Inflammatory Responses

Prostaglandin E2deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Lack of an Association between a Newly Identified Promoter Polymorphism (-1702G > A) of the Leukotriene C4 Synthase Gene and Aspirin-Intolerant Asthma in a Korean Population

Contact Info

Product

Resources

About

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes